Plasma-derived mannose-binding lectin shows a direct interaction with C1-inhibitor

Area of Science:

• Immunology
• Infectious Diseases
• Biochemistry

Background:

• Mannose-binding lectin (MBL) deficiency is linked to higher infection rates, particularly in vulnerable populations like pediatric cancer patients.
• MBL plays a crucial role in the innate immune system by initiating the lectin pathway of complement activation.

Purpose of the Study:

• To evaluate the safety and efficacy of plasma-derived MBL (pdMBL) substitution therapy in MBL-deficient pediatric oncology patients.
• To investigate the functional restoration of MBL activity in vivo and ex vivo following pdMBL administration.

Main Methods:

• An open, uncontrolled safety and pharmacokinetic study was conducted in MBL-deficient pediatric oncology patients receiving pdMBL.
• Ex vivo experiments involved testing pdMBL activity with MBL-deficient sera, assessing C4-converting activity, and analyzing the effects of MASP and C1-inhibitor (C1-inh) depletion or inhibition.

Main Results:

• Despite achieving target MBL trough levels, pdMBL did not efficiently restore MBL functionality in patients.
• PdMBL exhibited intrinsic C4-converting activity due to co-purified MASPs, which was reduced upon incubation with MBL-deficient sera.
• Depletion of MASPs from pdMBL or C1-inh from recipient serum restored C4-converting activity, indicating C1-inh neutralization of MBL-MASP complexes.
• Multimolecular complexes of C1-inh and MBL/MASPs (MMC-complexes) were detected post-infusion in patients, confirming in vivo interaction.

Conclusions:

• Plasma-derived MBL products contain active MBL-MASP complexes that are neutralized by C1-inh in the recipient.
• This interaction forms MMC-complexes, preventing efficient MBL-mediated complement activation and host protection.
• Current pdMBL products are unlikely to provide effective MBL-mediated immunity due to C1-inh neutralization of the incorporated MASPs.